5-halo-17(20)-bisnorcholenal compounds and process for preparing same



. ,INo Drawing.

acids and :aldehydes'starting' with stigmasterol. "gen in "the5og-halo-bisnorcholan aldehydesrepresentsa potential double bond and-yetis impervious to attack during the oxidation of the S-hydroxylgroup tothe -3-keto group.

'5-HALO-17(20)-BISNORCHOLENAL COMPOUNDS AND PRDCESS FOR PREPARING SAME fJohn M. Chemerda, Metuchen, Earl -M. Chamherlin,

Westfield, and Etiward W.- Tristram, Cranford, N. J., 'assignors'toMerck & Co.,.Inc., Railway, N. J., a corporation of New Jersey Griginalapplication December 2, 1954, Serial No. 472,756, now Patent No.2,777,843, dated "January 15, 1957. Dividedand this application November4, 1955, Serial No. 545,132

10 Claims. (Cl. 260-3974) This invention. relates to the preparation of4-pregnen- ,1'7a-ol-3,20-dione and particularly to the preparation of4-.pregnen-l7a-ol-3,29-dione from S-halo-bisnorcholerial,

.and tointermediates thus obtained.

.This application is a division of our copending applica- .tion.SerialNo. 472,756, filed December 2, 1954, now .-U. S. .Patent No. 2,777,843.

. Thediscovery of the remarkable propertiesof cortisone andhydrocortisoneand similar related co-mpounds',,has -stimulated wideinterest in finding simpler and more .economicalmethods of preparingsuch compounds. One

,. -of.the more recentmethods which has been developed for preparingthese valuable steroids is the introduction of LDX-ygengroups bysubjecting desoxy steroids tothe action yofwmicroorganisms. Thisdevelopment has led to' the in- Qcreasing importance of desoxy steroidswhich possess all the necessary groups with the exception of oxygengroups;

-which may be introduced by fermentation methods. One

, .of thernore valuable of these desoxy steroids is 4-pre-gnen-"17a.-ol-,3,20-dione which only lacks .the ll-keto and '21- hydroxygroups of cortisone,and the 116 and Zl-hydroxy gr.oups.ofhydrocortisone. .These oxygen groups can be added by fermenting thesteroid with various microorgan r .isms,.as forexarnple,fermentationwith variousstrains of Curvularia will introduce an llfi-hydroxy group,and

. vfermentation with various strains of Sphaeroidaceae will (introduce a21-hydroxy group.

:The preparation of. 4-pregnen-17a-ol-3,20-dionehas .hei:etofore .beencarried out by a costly and complex .processwhich involved theenolization of .bisnorcholenal l .followedby ozonization of theresulting enol ester, reduc- Qtive decomposition of the ozonidesto thecorresponding .2'1 keto-pregnane, enolization of this compoundto form...a ,A -2O-aceto-xy-pregnane, peracid oxidation of the [117,20 doublebond'to produce the 17,20 epoxide derivative of the unsaturatedestergand finallyihydrolysis of this 'compoundto produce4-pregnen-17wol-3,20-dione.

fIt hasb'eensuggested to prepare 5a-halo-bisnorcholanic The halo- Anobjecbof the invention is 'to provide a simplified --procedure "for:producing 4-pregnen-17a-ol-3,20vdione from readily available startingmaterial. Another object tates Patent 2,833,790 Patented .May. 6, 1958ice 11), dehydrobrominating to produce the.corresponding'5= halo 17(20)bisnorcholenal compound (Compound III),

treating. withperacid'to produce the corresponding epoxy formate(Compound .IV), hydrolyzing to'yield S-halo- .pregnane-3,17a-diol-20fone(Compound V), oxidation of theS-hydrOXy'gr up to form a keto group(Compound by saponification.

These reactions may'bechemic'ally represented wherein fR'is a groupconvertible to a hydroxy group by'hydrolysis and X is a halogenasfollows:

. 1 Compound :III

. ICE

-.OompoundVI V i 'scohjects ,and the advantagesrof :the. inventionvv'illtappear offthezinventionis .to provide aprocess for ;the degrada-'::tion ofthe aldehyde group in.SwhalmbishQrcholenalde: "oihyde :to:the::17a-hydroxyr20-keto sidechain without'rre- I J'nnoval'ofthe Smhalogmup 'Aifurther objectvis ,to-prowide valuable:intermediatesusefuldn this process. Other v.rhereinafter. a p

in 1 accordance with the :invention, 4-pregnen- 1711:01- cj3;20r-dione(Compound VII) is prepared by .the iollowing meries-zofrreactions:brominating a; 5,-halo-bisnorcholenal compound (Compound I) to producethe corresponding "A ;5:-halo4.20ab1iomodiisnorcholenal compound.(Compound g n The 5-halobisnorcholenal compound is brominated to producethe corresponding 5-halo-20-bromo-bisnorcholenal. TheS-halo-bisnorcholenal compound has either a Soc-ChlOIO or Sa-bromo groupand a substituent at the 3-position which may be readily hydrolyzed to ahydroxy group, such as an ether group of the formula R wherein R is ahydrocarbon group and especially a hydrocarbon radical containing up toand including eight carbon atoms, e. g. methyl, ethyl, propyl,isopropyl, butyl, hexyl, cyclohexyl, benzyl and the like, or an estergroup of the formula OCOR wherein R is a hydrocarbon radical, especiallyhydrocarbon radicals containing up to and including seven carbon atoms,such as methyl, ethyl, propyl, isopropyl, butyl, hexyl, heptyl, phenyl,cyclohexyl, and the like. I

The bromination may be conveniently carried out by dissolving orsuspending the S-halo-bisnorcholanal in an organic solvent andsubjecting the solution or suspension to the action of approximately anequal molar amount of bromine. There is sufficient hydrogen bromideformed during the reaction to act as a catalyst. It is preferred to usechloroform as a solvent, although other solvents may be used, such asacetic acid, formamide and mixtures of solvents, such as aceticacid-pyridine and acetic acid-formamide. The reaction temperaturegoverns the rate of bromination, thus the rate of bromination increasesat elevated temperatures. It is ordinarily desired, for convenience, toeffect the bromination at about 20 to 60 C. although temperatures as lowas 0 C. can be used under normal atmospheric pressure. Within thepreferred temperature range the reaction usually is complete in fromone-half to six hours.

The 5-halo-20-bromobisnorcholenal compound is readily dehydrobrominatedto produce the corresponding 5-halo-l7,(20)-bisnorcholenal. Thedehydrobromination can be readily carried out by heating with metallichalides particularly with lithium chloride in an amide solvent, such asan N,N-dialkylacylamide having the formula N-o-R'" wherein R and R arealkyl groups containing from one i dehydrobromination may also becarried out by the use 1 of collidine, pyridine, lutidine,diethylaniline, or other organic bases which are refluxed with thebromo-steroid for a period of time of the order of 15 minutes. The

product can be recovered by filtering, washing with water,

and drying.

The 5-halo-bisnorcholenal compound is converted directly to thecorresponding 5-halo-17,(20)-bisnorcholenal compound. This may bereadily carried out by reacting the bisnorcholanal with bromine in thepresence of a weak base. The weak base is preferably aN,N-dialkylacylamide having the formula wherein R, R" and R are asdefined above. Typical examples of such amides are:N,N-dimethylformamide N,N-dimethylacetamide, N,N-dimethylpropionamide,N,N-diethylformamide, N,N-diethylacetamide, N-methyl- N-ethylformamide,and N-methyl-N-ethylacetamide. The reaction time is reduced by theaddition of any of the ordinarily used bromination catalysts such ashydrogen bromide, sulfuric acid or organic sulfonic acids as for examplep-toluene sulfonic acid. The reaction is conveniently carried out atroom temperature which requires from 12 to 28 hours for completion. Theproduct can be recovered by diluting the reaction mixture with water,filtering, and then washing the product with water and drying.

The 5-halo-17,(20)-bisnorcholenal compound is treated with an organicperacid to produce the corresponding epoxy formate(Soc-halo-l7,20-epoxy-pregnan-20-ol-3-R- 20-formate). The organicperacid is preferably an aromatic percarboxylic acid, such as perbenzoicand perphthalic acids, and saturated aliphatic peracids, such asperacetic and persuccinic acids. This reaction results in nearlyquantitative yield of product. The reaction is preferably carried out inan organic solvent, such as benzene, chloroform, or ethylacetate. Thereaction is preferably carried at from minus 10 to 0, although thetemperature may be varied Within wide limits. At the preferredtemperature range the reaction requires from 12 to 48 hours forcompletion. The rate of reaction will vary with the temperature. Theproduct can be isolated from the reaction mixture by filtering to removevarious insoluble byproducts and reactants, and then washing withwatercontaining sodium carbonate. The organic layer is dried over sodiumcarbonate and evaporated to dryness under vacuum. The product can alsobe recovered by ether extraction followed by washing with dilute alkaliand water, and evaporating to dryness.

The 5a-halo-l7,20-epoxy-pregnan-20-ol-3-R-20 formate is hydrolyzed toyield 5-halo-pregnane-3,l7a diol-ZO-one. The hydrolysis is readilyachieved by treating with an acid in a suitable solvent, such asmethanol, ethanol, acetone, or tetrahydrofuran. Strong acid such ashydrochloric acid, sulfuric acid, perchloric acid, andpara-toluene-sulfonic acid, used in dilute concentrations are preferredfor effecting the hydrolysis. Temperatures ranging from about 0 to 80 C.are usually employed to accomplish the hydrolysis. At room temperature,several minutes to three hours are ordinarily adequate to complete thereaction. The heavy precipitate of product is filtered from the reactionmixture and washed with an tetrahydrofuran and the like.

organic solvent and dried under vacuum.

The epoxy formate is also converted to S-pregnene- 3,l7a-diol-20-one byreacting with a basic substance. Water must be present unless reactionis run in alcohol.

The reactants are preferably brought together in a solvent. Suitablesolvents are methanol, ethanol, hexane, benzene, toluene, xylene,petroleum ether, ether, dioxane, The basic substance may be any of theconventional bases, such as an alkali metal or alkali metal hydroxide,carbonates, bicarbonate or the like, but it is preferred to use anhydroxide as for example, sodium hydroxide, potassium methoxide, orpotassium hydroxide. The reaction may be carried out at from 0 to C. Atroom temperature the reaction requires from 30 to minutes forcompletion. On completion of the reaction the reaction mixture isneutralized by addition of an acid as for example, glacial acetic acid,and then the solution is partially concentrated by evaporation undervacuum. The product is precipitated from the reaction mixtureby additionof water and is then filtered and washed with water.

The 5-halo-pregnane-3,17a-diol-20-one is oxidized to produceS-halo-pregnan-17a-Ol-3,20-dione. The oxidation is preferably carriedout with a chromic anhydridepyridine complex, although other selectiveoxidizing agents may be used, such as chromic acid. The oxidation may becarried out at a wide range of temperatures, although preferably below50 C. Within the preferred temperature range, with the preferredoxidation agent, the reaction requires from 6 to 24 hours. The productcan be separated from the reaction mixture by conventional means.

The 5-halo-pregnan-17a-01-3,20-di0ne is treated with a gether inasolvent.

.ide.

1120-minutes for completion.

.um carbonate. .rated almost to dryness under vacuum and'100 millilitersC., [a] 13.4 (chloroform). 'C H O CiBr: C, 59.07;H, 7.44. Found:C,58.79;*H.

piss-swan basic substance to form 4-pregnan-17a ol 3;20-dione. Thisreaction is generally carried'out under anhydrous conditions. Thereactants are preferably brought tonol, hexane, benzene, toluene,xylene, petroleum ether, ether, dioxane, tetrahydrofuran and the like.The basic substance may be any of the conventional bases, such as-analkali or alkaline earth metal hydroxide, carbonate, bi- .carbonateor the like but it is preferred to use a hydroxide as for example,sodium hydroxide or potassium hydrox- The. reaction may be carried outat from to 70 C. At room temperature the reaction requires from 30 to Oncompletion of the reaction the reaction mixture is neutralized byaddition of an acid as for example, glacial acetic acid, and then thesolution is partially concentrated by evaporation under vacuum. Theproduct is precipitated from the reaction -ymixture--by addition ofwater and is then -filtered and washed with water.

The following examples are given for, purposes of illustration:

EXAMPLE 1 A solution of 14.5 grams (0.0354 mole) of Sfi-acetoxy-Sa-chIo-robisnorcholenal in 200 ml. of chloroform was treated with tengrams (0.1 mole) of anhydrous calcium carbonate and stirred at 28 C. Tothis slurry 46 milli- .litersof chloroform solution containing 5.5 grams(0.0344

mole) of bromine was added dropwise. over aperiod of one-half hour andthe reaction mixture stirred for two 1v hours. After filtering to removecalcium carbonate, the chloroform solution was washed with dilute sodiumiodide,

sodium thiosulfate solution and then with-dilute sodiumbicarbonatesolution and finally dried 'overanhydrous sodi- Thechloroform layer-was then-evapoof 95% ethanol was added. Upon furtherconcentration the main portion of product precipitated. After stand-,

ing overnight in the. refrigerator the product, *3fl-acetoxy- 5a chloro--br0mobisnorcholenaldehyde, was filtered, washed with 50 milliliters of95% ethanol and dried under vacuum; yield 10.6 grams, melting point 175.1 79 Analysis. Calc'd. for

EXAMPLE 2 3 fl-acetoxy-S a-clz lore-1 7 (20) -bisn0rch0lenalThirty-three grams (0.068 mole) of 38-acetoxy-5achloro-20-bromobisnorcholenal in 1320 milliliters ofdimethylformamide containing 5.5 grams (0.068 mole) of hydrogen bromidewas allowed to stand at 28 C. for four days. The solution was thenstirred and cooled in an ice bath while 600 milliliters of water wasadded. After stirring for three hours the product was filtered, washedwith water and dried under vacuum to yield 26.8 grams of essentiallypure 3B-acetoxy-5a-chloro-17(20)- bisnorcholenal,. melting point l94195C., A maximum 2540, E% 376. Recrystallization from methanol gave ananalytical sample with the same ultraviolet absorption. Analysis.Calcd.for C H O Cl: C, 70.82; H, 8.67; Cl, 8.71. Found: C, 70.51; H, 8.51; Cl,8.58.

EXAMPLE 3 3 fi-acetoxy-S a-chloro-l 7 (20) -bisn0rcholenal Two grams (5millimoles) of 3B-acet0xy-5a-chlorobisnorcholenaldehyde and 0.04 gram ofp-toluene sulfonic acid were dissolved in 80 milliliters ofdimethylformamide and stirred at 28 C. while 0.8 gram (5 millimoles) ofbromine in 7 milliliters of dimethylformamide was added dropwise overthe course of three hours. After standing at normal room temperature for24 hours the reaction mixture was cooled in an ice bath and diluted with80 milli- Suitable solvents are methanol, ethaeral reerysta-llizationsfrom ethanolgave productmelting product-showed no'depressionfiin meltingpoint when 'admixed with unsaturated aldehydeprepared' from@3;8=acetoxy-SB-chloro-20-bromo-bisnortrholenal.

EXAMPLE .4

3[3-acer0xy5a-chl0r0-17,20-epoxypregnan-20-ol fonmate A, solutioncontaining 15.7 grams (0.0386 mole) of 33-acetoxy-5a-chloro-17,(20)-bisnorcholenaldehyde in 150 milliliters ofdry benzene at 10C. was treated with 56 grams (0.309 mole).ofiperphthalic acid in435 milliliters of ethyl acetate. The reactionmixture, after stand- 'ing'two days at .normal room temperature,wasi'filtered to removeinsoluble phthalic acidand washed four times with500 milliliters of 10% sodium carbonate solution. The organic layer wasdried over sodium carbonate and evaporated to dryness under vacuum toyield.15.1 grams;

melting point 139142'C.; [a] 5.2 (chloroform). Theinfrared spectrumof'the crude reaction product was. compatible with'the epoxy fformateformulation and elemental analysis agreed with calculated values.Analysis.Calcd. for"C ;H O Cl: C,- 65.66; H, 8.04; Cl,- 8.08. Found: C,65.64; H, 7.97; Cl,-l8.l 2.

One gram (2.4 millimoles) of 3fi-acetoxy-5a-chloro-17,20-epoxypregnan-20-ol.formate was dissolved in 150 milliliters ofethanol at 30 C. and treated with 30 milliliters of 2.5 M sodiumhydroxide solution. After standing for ninety-minutes at normal roomtemperature 6 milliliters of glacial acetic acid was added and thesolution was partially evaporated under vacuum. The prod uct wasprecipitated by dilution with 75 milliliters of water and refrigeratedovernight. The reaction mixture was filtered;.the solid was washedwithwater and dried under vacuum to yield'j0.5'5. gram of product, 5-pregnene- 3B,17a-diol-20-one, melting 'at 2002l5 C. Recrystallizationfrom ethanol gave product melting at 20S-210 C. which was not depressed.upon mixture with authentic 5 pregnene -3fi,17zx diol 20 one.Analysis.-Calcd.

EXAMPLE 6 5 a-chl0r0pregnane-3 5,1 7a-a'i0Z-20-0ne A slurry of 2.5 grams(5.7 millimoles) of 3 8-acetoxy- Sa-chloro-17,20-epoxypregnane-20-olformate in ml. of methanol was treated at normalroom temperature with12.5 milliliters of concentrated hydrochloric acid. A greenish-bluecolor developed and within an hour solution was practically complete.The reaction mixture was allowed to stand overnight and then was cooledfor one hour in the refrigerator. The heavy precipitate of product,5u-chloropregnane-3fl,17a-diol-20-one, was filtered, washed withmethanol and dried under vacuum; weight 1.0 gram, melting point 200 205C. Boiling with ethyl acetate dissolved little of the product but raisedthe melting point to 205 -210 C. The infrared spectrum showed hydroxylat 2.82,:1. and 2.98 carbonyl at 5.90 1 and no acetate grouping.Rotation in pyridine solution M1 +1 C. Analysis.-Calcd. for C H O Cl: C,68,36; H, 9.02; Cl, 9.61. Found: C, 68.33; H, 9.03; Cl, 9.51.

EXAMPLE 7 4 -pregnen-J 7u-0l-3,20-di0l18 A chromic anhydride-pyridinecomplex was formed by adding 1.3 grams (13 millimoles) of chromicanhydride in small portions with stirring to 13 milliliters of pyridinewhile keeping the temperature below 25 C. To this stirred slurry wasadded 1.3 grams (3.5 millimoles) of a-chloropregnane-3fi-17a-diol-20-onein 26 milliliters of pyridine. No heat of reaction was observed butwithin one-half hour the mixture had become dark brown. After stirringovernight the reaction was poured into 500 milliliters of dilute sodiumhydroxide solution. The precipitated product5u-chloro-pregnan-17a-ol-3,20-dione was stirred for one hour, filteredand washed with water.

The product was dissolved in 25 milliliters of pyridine and 50milliliters of methanol, filtered to remove insoluble inorganic materialand treated with milliliters of 2.5 molar sodium hydroxide solution atroom tempera ture for one hour. The reaction mixture was then dilutedwith 100 milliliters of water and refrigerated for one hour. Filtrationof the solid precipitate, followed by washing with water and dryingunder vacuum yielded 0.6 gram of 17a-hydroxyprogesterone, melting point2002l2 C., A maximum 2420 A., E% 488. A sample for analysis 'wasrecrystallized from ethanol, melting point 213-218 C. Identity of thesample with authentic material was established by infrared analysis andmixed melting point. Analysis.Calcd. for C H O C, 76.32; H, 9.15. Found:C, 76.77; H, 9.58.

Any departure from the above description which conforms to the presentinvention is intended to be included in the scope of the claims.

What is claimed is:

1. Compounds having the structural formula:

wherein R is selected from the class consisting of radicals having theformula ---OR and wherein R and R are hydrocarbon groups containing lessthan nine carbon atoms and X is a halogen.

2. 3 fi-acetoxy-S a-chloro- 1 7 20) -bisnorcholen al.

3. A process which comprises reacting with a dehydrobrominating agent a3-R-5-halo-20-bromo-bisnorcholenal compound wherein R is selected fromthe class consisting of radicals having the formula -O-R and wherein Rand R are hydrocarbon groups containing less than nine carbon atoms toform the corresponding 5 -halo-l7 (20) -bisnorcholenal.

4. A process which comprises reacting a 3-R-S-halobisnorcholenalcompound wherein R is selected from the class consisting of radicalshaving the formula OR and O('i-R wherein R and R are hydrocarbon groupscontaining less than nine carbon atoms, with bromine in the presence ofa weak organic base to produce the corresponding 5-halo-l7(20)-bisnorcholenal compound.

5. The process of claim 4 wherein the weak organic base is anN,N-dialkylacylamide.

6. The process of claim 4 wherein the reaction with bromine is carriedout in the presence of a bromination catalyst.

7. The process of claim 6 wherein the bromination catalyst is hydrogenbromide.

8. The process of claim 5 wherein the N,N dialky1- acylamide isdimethylformamide.

9. A process which comprises reacting3/3-acetoxy-5achloro-bisnorcholenal with bromine in the presence ofhydrogen bromide and dimethylformamide to form 3,8

acetoxy-5a-chloro- 17 20 -bisnorcholenal.

10. A process which comprises reacting3}8-acetoxy-5achloro-20-bromobisnorcholenal with hydrogen bromide indimethylformamide to form 3 8-acetoxy-5a-chloro- 17(20)-bisnorcholenal.

References Cited in the file of this patent UNITED STATES PATENTS KrsekJan. 24, 1956

1. COMPOUNDS HAVING THE STRUCTURAL FORMULA: